1. Field of the Invention
The present invention relates to novel peptides comprising TGF-β-originated peptides and their uses.
2. Description of the Related Art
Transforming growth factor-beta (TGF-β) is a group of polypeptide growth factors regulating cell division and differentiation. This group also includes Mulleria inhibitor (Cate et al., 1986, Cell, 45:685-698), inhibins (Mason et al., 1985, Nature, 318:659-663), and Drosophilla DPP-C (decapentaplegic gene complex) protein (Padgett et al., 1987, Nature, 325:81-84). TGF-β consists of two similar disulfide-linked subunits each having a molecular weight of 13,000 daltons (Assoian et al., 1983, J. Biol. Chem. 258:7155-7160; Frolik et al., 1983, Proc. Natl. Acad. Sci. USA 80:3676-3680; Frolik et al., 1984, J. Biol. Chem. 260:10995-11000). TGF-β has been isolated from several tissues, including placenta (Frolik et al., 1983, Nature 325:81-84), human platelet (Childs et al., 1982, Proc. Natl. Acad. Sci. USA 79:5312-5316, Assioan et al., 1983, J. Biol. Chem. 258:7155-7160), kidney (Roberts et al., 1983, Biochemistry 22:5692-5698), and bovine demineralized bone (Seyedin et al., 1985, Proc. Natl. Acad. Sci. USA 82:119-123).
TGF-β is able to increase anchorage-independent growth of normal rat kidney fibroblast in the presence of 10% serum and epidermal growth factor (Roberts et al., 1981, Proc. Natl. Acad. Sci. USA 78:5339-5343; Roberts et al., 1982, Nature 295:417-419; Twardzik et al., 1985, J. Cell Biochem. 28:289-297), and to induce colonies of AKR-2B fibroblast in only 10% serum (Tucker et al., 1983, Cancer Res. 43:1518-1586). Also, it could cause differentiation of muscle mesenchymal cells and generation of cartilage-specific macromolecules in fetal rats (Seyedin et al., 1986, J. Biol. Chem, 261:5693-5695). In contrast to the positive effects on cell proliferation, not only function-related proteins isolated from African green monkey kidney epithelial cells (BSC-1) but TGF-β purified from human platelet could inhibit cell growth during cell culture (Tucker et al., 1984, Science 226:705-707). In addition, TGF-β inhibits the growth of some human tumor cells (Roberts et., 1985, Proc. Natl. Acad. Sci. USA 82:119-123). These inhibitory or stimulatory effects of TGF-βs have been reported to be dependent on several factors such as cell morphology and cell physiological conditions (Spon et al., 1986, Science 232:534).
TGF-β cDNA clones were isolated from human (Derynck et al., 1985, Nature 316:701-705), mouse (Derynck et al., 1986, J. Biol. Chem. 261:4377-4379), and simian virus 40 (Sharples et. al., 1987, DNA 6:239-244). By analyzing their DNA sequences, it was reported that TGF-β was synthesized as a precursor polypeptide, and then spliced to TGF-β monomer. The TGF-β precursor proteins described above exhibit high homology in their amino acid sequences.
Recently it was identified that a protein isolated from bovine demineralized bone was related to TGF-β (Seyedin et al., 1987, J. Biol. Chem., 262: 1946-1949). It was also isolated from other species, containing porcine blood platelets (Cheifetz et al., 1987, Cell 48:409-415), human prostatic adenocarcinoma cell line PC-3 (Ikeda et al., 1987, Biochemistry 26:2406-2410), and human glioblast cell (Wrann et al., 1987, EMBO 6:1633-1636). Because the partial amino acid sequence of this protein is homologous to that of TGF-β, it was named as TGF-β2. TGF-βs isolated from human (Derynck et al., 1985, Nature 316:701-705), mouse (Derynck et al., 1986, J. Biol. Chem. 261:4377-4379), and simian virus 40 (Sharples et. al., 1987, DNA 6:239-244) were named as TGF-β1.
TGF-β1 is a highly active protein. Unfortunately, its utilization and application have not yet become widened because of its poor expression, high production cost and short half-life.
Throughout this application, various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.